EP0733033A1 - Pharmazeutisch aktive substituierte aromatische verbindungen - Google Patents

Pharmazeutisch aktive substituierte aromatische verbindungen

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Publication number
EP0733033A1
EP0733033A1 EP95933542A EP95933542A EP0733033A1 EP 0733033 A1 EP0733033 A1 EP 0733033A1 EP 95933542 A EP95933542 A EP 95933542A EP 95933542 A EP95933542 A EP 95933542A EP 0733033 A1 EP0733033 A1 EP 0733033A1
Authority
EP
European Patent Office
Prior art keywords
benzyloxy
alkyl
propyl
methyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP95933542A
Other languages
English (en)
French (fr)
Other versions
EP0733033B1 (de
Inventor
Gloria Ann Breault
John Oldfield
Howard Tucker
Peter Warner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syngenta Ltd
Original Assignee
Zeneca Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Publication of EP0733033A1 publication Critical patent/EP0733033A1/de
Application granted granted Critical
Publication of EP0733033B1 publication Critical patent/EP0733033B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/34—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
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    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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Definitions

  • This invention relates to novel, aromatic compounds and pharmaceutically-acceptable salts thereof which possess useful pharmacological properties. More particularly the compounds of the invention are antagonists of the pain enhancing effects of E-type prostaglandins.
  • the invention also relates to processes for the manufacture of the aromatic compounds and pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to use of the compounds in pa n relief.
  • the compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis) , postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis) , the pain associated with burns (including sunburn) , the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget's disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly or in part play a pathophysiological role.
  • pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis) , postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis) , the pain associated with burns (including sunburn) , the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget's
  • Non-steroidal anti-inflammatory drugs and opiates are the main classes of drugs in pain relief. However both possess undesireable side effects. NSAIDS are known to cause gastrointestinal irritation and opiates are known to be addictive.
  • the compounds of the invention may also possess anti-inflammatory, anti-pyretic and anti-diarrhoeal properties and be effective in other conditions in which prostaglandin E (PGE ) wholly or in part plays a pathophysiological role.
  • PGE prostaglandin E
  • A is optionally substituted: phenyl, naphthyl or a 5- or 6-membered heteroaryl ring system containing no more than two ring nitrogen atoms or thiadiazolyl or a bicyclic ring system of the formula:
  • E is nitrogen or CH
  • F is nitrogen or CH
  • G is sulphur or oxygen
  • H is nitrogen or CH
  • the -Z- and -0CH(R )- groups are positioned in a 1,2 relationship to one another on ring carbon atoms; and provided that the ring atom in the 2-position relative to the ring carbon atom bearing the -0CH(R )- group and in the 3-position relative to the ring carbon atom bearing the -Z-B-R group is unsubstituted and, when A is naphthyl, either the -Z-B-R group is in the 1-pos ⁇ t ⁇ on and the -OCH(R )- group is in the 2-pos ⁇ t ⁇ on of the naphthyl group and the ring atom in the 3-pos ⁇ t ⁇ on is not substituted, or the -Z-B-R - group is in the 2-position and the -0CH(R )- group is in the 3-position of the naphthyl group and the ring
  • B is an optionally substituted 5- or 6-membered heteroaryl ring system, optionally substituted phenyl or an optionally substituted ring system of the formula:
  • D is optionally substituted: phenyl cr a 5- or 6- membered heteroaryl ring system
  • R is carboxy, optionally substituted tetrazolyl, carboxyC alkyl, optionally substituted tetrazolylC alkyl, hydroxamic acid, sulphonic acid, tetronic acid cr a pharmaceutically acceptable amide (-CONR-), reverse amide (-NRCC-), acylsulphonamide
  • acylhydrazide (-CON(R)N ) or C alkyl substituted by a 2 1-4 pharmaceutically-acceptable amide, reverse amice, acylsulphonamide or acylhydrazide or R is of the formula (IIA) , ("B) or (IIC) :
  • X is CH or nitrogen
  • Y is oxygen or NH
  • Z is CH , NH or oxygen
  • Y is oxygen or sulphur provided that there is no more than one ring oxygen and there are at least two ring heteroatoms;
  • p and q are independently 0, l or 2 providing p+q is not greater than 2, one of r and s is 0 and the other s 1 and t and u are independently 0, 1, 2 or 3 providing t + u s not less than 1 or greater than 3; and R is hydrogen, methyl, ethyl, hydroxy, me noxy or ethoxy; and N-oxides where chemically possible; and S-oxides where chemically possible; and pharmaceutically acceptable salts and in vo hydrolysable esters and amides thereof .
  • Particular pharmaceutically acceptable amides are, for example, for
  • R is hydrogen, C alkoxycarbonyl, hydroxy or optionally substituted: C alkyl, C alkenyl,
  • 6-membered heteroarylC alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl, ⁇ - or 6-membered saturated or partially saturated heterocyclylc alkyl, 5- or 6-membered heteroarylium or 5-
  • 5- or 6-membered heteroarylium rings are pyridmium, pyriminidinium, pyrazinium, pyridazinium and imidazollum.
  • R is of the formu a OR wherein R is hydrogen, optionally substituted C alkyl, 5- or 6-membered monocyclic heteroaryl or a 5- 1-6 or 6-membered monocyclic saturated or partially saturated heterocyclyl,
  • R is of formula NR ?. wherein R is hydrogen or C alkyl and
  • R is optionally substituted alkyl or R is optionally substituted
  • acylhydrazides are, for example of the forrula
  • R is as hereinabove defined, R is hy ⁇ rogen
  • R is hydrogen, hydroxy or optionally substituted:
  • 6-membered heteroaryl 5- or 6-membered heteroarylC alkyl, 5- or
  • R 16 and R17 together with the nitrogen atom to which they l ' a 6 re attached, form a 4 to 8-membered saturated or partially saturated heterocyclic ring or form an ammo acid residue or ester thereof
  • a 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur.
  • a 5- or 6-membered saturated or partially saturated heterocyclyl is a ring system having 5 or 6 ring atoms wherein , 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulpnur
  • a 4 to 8-membered saturated or partially saturated heterocyclic ring is a ring system having 4 to 8 ring atoms wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen ana sulphur.
  • Particular 5- or 6-membered heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyn ⁇ yl, pyrazinyl, pyrimid yl, pyridaz yl, thiazolyl, thiadiazolyl, t.iienyl, furyl and oxazolyl.
  • Particular 5- or 6-membered saturated or partially saturated heterocyclic ring ring systems include pyrrolidinyl, pyrrol yl, imidazolidinyl, pyrazolidmyl, piperidyl, piperazmyl and morpr.clinyl
  • An 8-10 bicyclic heteroaryl is a bicyclic aryl ring system having 8 to 10 ring atoms wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen and sulphur.
  • 1-6 ami ⁇ es, reverse amides, acylsulphonamides and acylhydrazides are hydroxy, amino, C alkoxy, halo, C alkoxvcarDonyl, C alkylS (0) - 1 1-4 1-4 1-4 p
  • 6-membered monocyclic heteroaryl 6-membered monocyclic heteroaryl, tetrazoiyl, a 5- or 6-membered saturated or partially saturated heterocyclic ring and 5- or 6-membered monocyclic heteroarylium.
  • substituents for ring systems in amides and reverse amides include, halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C alkylS (0) - (p is 0, 1 or 2) , carbamoyl, C alkanoylammo, 1-4 p 1-4
  • Suitable ring systems of the fcrmula (IIA) , (IIB) or (IIC) include 5-oxo-4, 5-d ⁇ hydro-l, 2, -oxad ⁇ azole-3-yl, 3-oxo-2,3- d ⁇ hydro-1, 2,4- oxad ⁇ azole-5-yl, 3-th ⁇ oxo-2 , 3-d ⁇ hydro-l,2,4-oxad ⁇ azole- 5-yl, 5-OXO-4, 5-d ⁇ hydro-l,3 ,4-oxad ⁇ azole-2-yl, 5-OXO-4, 5-d ⁇ hydro-l,2, 4-t ⁇ azole-3-yl, 3-oxo-2, 3-d ⁇ hydro ⁇ soxazole-5-yl,
  • Amino acid residues formed from R and R or R and R together with the amide nitrogen to which they are attached and esters c d thereof include for example radicals of tne formula -NH-CH(R ) -COOR wherein R is hydrogen, C alkyl, C alkenyl, C alkynyl, phenyl,
  • R is hydrogen or C alkyl, wherein alkyl, 1-3 1-6 alkenyl, alkynyl, phenyl and heteroaryl groups are optionally substituted.
  • substituents include those mentioned above for ring A In particular hydroxy.
  • substituents for ring carbon atoms in A include halo, trifluoromethyl, nitro, hydroxy, amino, C alkylamino, di [C alkyl]amino, cyano, C alkoxy, carboxy, allyloxy, 1-4 1-6
  • suitable substitutents include tetramethylene and diradicals of the formula
  • Particular substituents for ring carbon atoms in B include halo, trifluoromethyl, nitro, hydroxy, C alkoxy, C alkyl, amino,
  • Particular optional substituents for D are halo, trifluoromethyl, nitro, hydroxy, ammo, C alkylamino, d ⁇ (C alkyDamino, C alkanoylammo, cyano, C alkoxy, allyloxy,
  • -S(O) C alkyl 'p is 0, 1 or 2) , C alkanoyl or C alkyl optionally p l-4 1-4 1-4 substituted by hydroxy, nalo, nitro, cyano and amino.
  • sucstituents for tetrazole groups include C
  • alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
  • substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
  • hydroxyiminoC alkyl includes
  • the invention also includes tautomers.
  • 2-hydroxypyridine includes 2-pyridone.
  • Examples of C 1—6alkoxycarbonyl are ethoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxyC alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxyprcpyl; examples of C alkoxycarbonylC alkyl are methoxycarbonylmethyl,
  • examples of tetrazolylC alkyl are tetrazolylmethyl and 2-tetrazolylethy
  • examples of C alkoxy are methoxy, ethoxy, propoxy and isoprcpoxy
  • examples of C alkenyl are vinyl and allyl
  • 2 ⁇ o 2—o are ethynyl and propynyl; examples of C alkanoyl are formyl, acetyl, propionyl and butyryl; examples of halo are fluoro, chloro, bromo and iodo; examples of C alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di(C alkyDamino are dimethylamino, diethylamino and ethylmethylamino; examples of
  • C alkyl are methylthio, methylsulphinyl and methylsul honyl;
  • p 1-4 examples of C alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl;
  • 1-4 examples of di (C alkyl)carbamoyl are dimethylcarbamoyl, 1-4 diethylcarbamoyl and ethylmethylcarbamoyl;
  • examples of C alkyl are
  • C cycloalkyl 1-6 methyl, ethyl, propyl and isopropyl; examples of C cycloalkyl are cyclopropyl, cyclobutyl and cyclohexyl; examples of
  • C cycloalkylC alkyl are cyclopropylmethyl and cyclohexyi .ethyl; examples of C cycloalkylC alkenyl are cyclopropylethenyl and cyclopentylpropenyl; examples of C cycloalkylC alkynyl are cyclopropylethynyl and cyclopentylethynyl; examples of C alkenyl are cyclopentenyl and cyclohexenyl; examples of C cycloalkenylC.
  • alkyl are cyclopentenylmethyl and cyclohexenylmethyl; examples of C cycloalkenylC alkenyl are cyclohexenylethenyl and cycloheptenylethenyl, examples of C cycloalkenylC alkynyl are cyclopentenylethynyl and cyclohexenylethynyl, examples of
  • C alkoxycarbonyiamino are methoxycarbonylamino and ethoxycarbonylamino; examples of C alkanoylammo are acetamido and propionamido; examples of C alkanoyl (N-C alkyDamino are
  • C alkanesulphonamido are methanesulphonamido and ethanesulphonamido;
  • examples of C alkylaminosulphonyl are methylammosulphonyl and ethylaminosulphonyl;
  • examples of d ⁇ (C alkyl)ammosulphonyl are dimethylammosulphonyl, diethylaminosulphonyl and ethylmethylaminosulphonyl,
  • examples of C alkanoyloxy are acetyloxy and propionyloxy;
  • examples of formylC alkyl are formylmethyl and
  • C alkoxyiminoC alkyl examples of C alkoxyiminoC alkyl are methoxyiminomethyl, ethoxyimmomethyl and 2- (methoxyimmo)ethyl.
  • A is optionally substituted: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazmyl, pyridazmyl, oxazolyl, thienyl, thiadiazolyl or thiazolyl.
  • ring systems of the formula (IA) are of the formula:
  • r ng systems of the formula (IB) are of the formula:
  • R is methyl
  • B is optionally substituted: phenyl, pyridyl, thiazol l, thienyl, thiadiazolyl, imidazolyl, oxazolyl, pyrazmyl, pyridazmyl, pyrimidinyl, pyridone, pyridazmone, furan, pyrrole or pyrimidinone.
  • D is phenyl, thienyl, furyl, pyridyl, thiazolyl or oxazolyl.
  • A is optionally substituted: phenyl, thienyl naphthyl or thiadiazolyl.
  • A is optionally substituted: phenyl, thienyl or naphthyl.
  • B is optionally substituted pyridyl, phenyl, thiazolvl, thienyl, pyrazinyl, oxazolyl, pyridazmyl or 2-pyridone optionally substituted on the ring nitrogen by a methyl group.
  • D is optionally substituted: phenyl, thienyl or furyl.
  • D is phenyl it is unsubstituted or substituted in the meta- or para- position.
  • A is optionally substituted phenyl.
  • B is optionally substituted: phenyl, pyridyl, or 2-pyridone optionally substituted on the ring nitrogen by a methyl group.
  • D is optionally substituted phenyl.
  • R is optionally substituted tetrazolyl, carboxyC alkyl, optionally substituted tetrazolyl alkyl, hydroxamid acid, sulphonic acid, tetronic acid or a pharmaceutically acceptable amide, reverse amide, acylsulphonamide cr C, alkyl
  • compositions are, of the formula
  • X—b hydrogen, C alkoxycarbonyl, hydroxy, optionally substituted 1-6
  • compositions are of:
  • R is of fcrmula NR R wherein R s hydrogen or C alkyl and R s octionally substituted
  • a yl sulphonamides are preferred.
  • R is carboxy, optionally substituted tetrazolyl, carboxymethyl, optionally substituted tetrazolylmethyl, hydroxamic acid, sulphonic acid, tetronic acid or of the formula
  • C alkyl and R is hydrogen, C alkoxycarbonyl, hydroxy, optionally 1-4 1-6 substituted: C alkyl, cycloprcpylC alkyl, cyclobutylC alkyl, cyclopenylC alkyl, cyclohexylC. alkyl, pyridylC alkyl, pyrimidylC alkyl, pyrazmylC, ,alkyl, pyridazmylC alkyl,
  • R is of the formula -NR COR cr -CH NR COR wherein R s hereinabove defined and R is hydroxy, py ⁇ dyloxy, py ⁇ midyloxy, pyrazinyloxy, pyridazmyloxy, optionally substituted C alkoxy, optionally
  • R ⁇ is carboxy, optionally substituted tetrazolyl, carboxymethyl, optionally substituted tetrazolylmethyl or
  • R is hy ⁇ rogen, C alkoxycarbonyl, hydroxy
  • C alkyl (optionally svibstituted by one or two substituents selected 1-6 from hydroxy, amino, C alkoxy, halo, C alkoxycarbonyl,
  • R is hydroxy, pyndyloxy, c alkoxy (wherein the alkyl
  • 1-6 group is cptionally substituted by hydroxy, amino , halo , cyano ,
  • R is carboxy, tetrazolyl, methanes lphonylaminocarbonyl, benzenesulphonylaminocarbonyl, (optionally substituted on the phenyl ring by nitro, hydroxy, halo, am o, C. alkyl, C alkoxy, cyano ot trifluoromethyl), or R s of
  • Preferred optional substituents for ring carbon atoms m A are hale, nitro, trifluoromethyl, cyano, am o, C alkoxy, carcamoyl,
  • A when A is a 6-membered ring, it is unsubstituted or substituted in the 4-pos ⁇ t ⁇ on relative to the -0-CH(R )- linking group.
  • Preferred optional substituents for ring carbon atoms m B are hydrc::y, halo, methoxy, cyano, trifluoromethyl, ammo, N-methyla-.mo or N,N-d ⁇ methylam ⁇ no.
  • Preferred optional substituents for D are halo, nitro hydroxy, cyano, methyl, ammo, methoxy or carbamoyl.
  • A is unsubstituted or substituted by one substituent.
  • B is unsubstituted cr substituted by one substituent.
  • D is unsubstitued.
  • R is hydrogen.
  • R , R , and Z are as hereinabove defined, R s hydrogen, halo, trifluoromethyl, nitro, hydroxy, amino, C. alkylamino, di [C alkyl]amino, cyano, C alkoxy, carboxy, allyloxy, 1-6 1-6
  • C alkyl (optionally substituted by hydroxy, C. alkoxy, amino, halo, 1—6 ——4 nitro, S(O) C alkyl (p is 0, 1 or 2) , S O) -p ⁇ enyl (p is 0, 1 or 2) p 1-4 p or cyano) , carbamoyl, C alkylcarbamoyl, di (C alkyl) carbamoyl,
  • the invention includes in its definition of active ingre ⁇ ient any such optically active or racemic form which possesses anti-hyperalgesic properties.
  • the synthesis of optically active forms r_ay be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the pain relieving effects may be evaluated using the standard laboratory techniques referred to hereinafter.
  • An m vivo hydrolysable ester or amide of a compound of the formula (I) containing carboxy group is, for example, a pharmaceutically acceptable ester or amide which is hydrolysed in the human or animal body to produce the parent acid, for example, a pharmaceutically acceptable ester or amide formed with a (1-6C)alcohol such as methanol, ethanol, ethylene glycol, propranol or butanol, or with a phenol or benzyl alcohol such as phenol or benzyl alcohol or a substituted phenol or benzyl alcohol wherein the substituent is, for example, a halo (such as fluoro or chloro) , (l-4C)alkyl (such as methyl) or (1-4C)alkoxy (such as methoxy) group.
  • a halo such as fluoro or chloro
  • (l-4C)alkyl such as methyl
  • (1-4C)alkoxy such as methoxy
  • a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention whicn is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a tricyclic heterocycle of the invention which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium cr magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, t ⁇ methylamine, piperidme, morpholme or tris- (2-hydroxyethyl)amine.
  • the invention provides a process for preparing compounds of the formula (I) or pharmaceutically acceptable salts or in vo hydrolysable amides or ester thereof, which comprises deprotecting a compound of the formula (VI)
  • R is R or protected R , R , Z, n, A, B and D are as hereinabove defined, and any optional substituents are optionally protected and at least one protecting group is present; and thereafter if necessary:
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a suitable protecting group for a hydroxy group is, for example, an arylmethyl group (especially benzyl) , a tri- (1-4C)alkylsilyl group (especially trimethylsiiyl or tert-butyldimethylsilyl) , an aryldi- (1-4C)alkylsilyl group (especially dimethylphenylsilyl) , a diaryl- (1-4C)alkylsilyl group (especially tert-butvldiphenylsilyl) , a (l-4C)alkyl group (especially methyl), a (2-4C)alkenyl group (especially allyl) , a (1-4C)alkoxymethyl group (especially methoxymethyl) or a tetrahydropyranyl group .especially t etrahydroyran-2-yl) .
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
  • a trialkylsilyl or an aryldialkylsilyl group such as a tert-butvldimethylsilyl or a dimethylphenylsilyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid, or with an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride.
  • a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid
  • an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride.
  • an alkyl group may be removed, for example, by treatment with an alkali metal (1-4C)alkylsulphide such as sodium thioethoxide or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide or, for example, by treatment with a boron or aluminium trihalide such as boron tribromide.
  • an alkali metal (1-4C)alkylsulphide such as sodium thioethoxide
  • an alkali metal diarylphosphide such as lithium diphenylphosphide
  • a boron or aluminium trihalide such as boron tribromide.
  • a (1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric or trifluoroacetic acid.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl) or an aroyl group (especially benzoyl) .
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl) .
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl, alkoxycarbonyl or aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (1-4C)alkyl group (especially methyl or ethyl) which may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide; or, for example, a tert-butyl group wnich may be removed, for example, by treatment with a suitable acid sucn as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide
  • a tert-butyl group wnich may be removed, for example, by treatment with a suitable acid sucn as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
  • A, B, D, R , R , R , and n are as hereinabove defined and one of r and s is o and the other is 1;
  • A, B, D, R , R , R , p, q and n are as hereinabove defined and R 23-R25 are independently C alkyl or optionally substituted phenyl;
  • A, B, D, R , R , R , n, r and s are as hereinabove defined; and thereater if necessary: i) removing any protecting groups; ii) forming a pharmaceutically acceptable salt; iii) forming an in vivo hydrolysable ester or amide; iv) converting an optional substituent into another optional substituent.
  • R include cyano, carbamoyl, alkoxycarbcnyl, carboxy and activated carboxy groups such as acid chlorides and activated esters.
  • the cyano group may be converted into a tetrazole ring by reacting, for example, with ammonium or tin azide in an aprotic solvent such as DMF, in a temperature range of 100°C to 130°C.
  • an aprotic solvent such as DMF
  • Alkoxycarbonyl may be converted into a carboxy group ry acid or base hydrolysis.
  • base hydrolysis may be carried out in an organic solvent such as methanol or THF in a temperature range of ambient to 100°C, in the presence of sodium hydroxide or potassium hydroxide.
  • Acid hydrolysis may, for example, be carried out or m neat formic acid or neat trifluoroacetic acid optionally in an organic solvent such as dichloromethane.
  • An alkoxycarbonyl or an activated carboxy group, sucr. as an acid chloride or activated ester, or an acyl group such as an alkanoyl group may be converted to an amide group by reacting with the appropriate amine in an inert solvent such as DMF or dichloromethane, in a temperature range of 0°C to 150°C, preferably around ambient temperature, in the presence of a base such as triethylamine.
  • an inert solvent such as DMF or dichloromethane
  • the compounds of the formula (VII) may be prepared using processes b) , c) , d) , e) , f) or g) from the appropriate starting
  • the compounds of the formula (VIII) may be reduced under standard conditions known in the art for the reduction of olefins, for example, catalytic hydrogenation using Raney nickel, platinum metal or its oxide, rhodium, zinc oxide, palladium-on-charcoal or Wilkinson's catalyst [RhCKPh P) ] as the catalyst.
  • Catalyst hydrogenation is conveniently carried out in the temperature range 0°C to 150°C, but preferably at ambient temperature at slightly above atmospheric pressure, unless the double bond is highly substituted in which case higher temperatures and pressure may be required, or Wilkinson's catalyst in which case a temperature of approximately 50°C and pressure of approximately 50 atmospheres are preferable.
  • the double oond may be hydrogenated catalytically using Wilkinson's catalyst and then the ketone group reduced, if appropriate, by forming the tosyl hydrazone and reducing with sodium borohydride.
  • the compounds of the formula (IX) are conveniently prepared by reacting a compound of the formula (XVII) with a compound of the formula (XVIII) . Suitable reaction conditions are described below
  • Suitable leaving groups include hale, for example, chloro, bromo or i ⁇ do, and tosylate and esylate.
  • the reaction is performed in an inert solvent such as hexane, tetrahydrofuran or ethyl ether, in a temperature range of o -100 C to ambient temperature, in the presence of a strong base such as butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide (LSA) or lithium hexamethyldisilylamide, preferably in the presence of a hindered base such as LDA or lithium hexamethyl disilylamide.
  • a strong base such as butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide (LSA) or lithium hexamethyldisilylamide
  • LDA lithium diisopropylamide
  • LDA hindered base
  • the leaving group is bromo, in tetrahydrofuran in the presence of LDA at 30 C.
  • the compounds of the formula (X) are ⁇ conveniently prepared by reacting a compound of the formula (XVI) with a compound of the formula
  • a and R are as hereinabove defined and P is a hydroxy protecting group, and thereafter deprotecting the hydroxy group and converting it to a leaving group (L) .
  • Conversion of the hydroxy group to a leaving group s performed by standard processes known in the art. For example when the leaving group is bromo, reacting the hydroxy group with phosphorous tr bromide.
  • R -R are all the same.
  • R -R are all phenyl.
  • XXI (scheme I)
  • Deprotonation is usually carried out in an inert solvent such as tetrahydrofruan or diethyl ether, in a temperature range of -78°C to ambient, in the presence of a strong base.
  • strong bases are lithium hexamethyldisilylamide, CH SOCH Na and butyl lithium.
  • Suitable values for L include halogen, such as chloro, bromo or iodo.
  • an inert solvent such as acetonitrile, diethyl ether, tetrahydrofuran or toluene is used and a temperature range of 50°C or 120°C.
  • the compounds of the formula (XXII) may be known or prepared from another compound of the formula (XXII) or a compound of the formula (XXIV) :
  • (XXII) wherein L is hydrcxy, may then be converted to a compound of the formula (XXII) wherein L ⁇ is bromo by, for example, bromonating with N-bromosuccinimide.
  • reaction between compounds of the formulae (XI) and (XZV) is conveniently performed in the presence of a base such as butyl lithium, sec-butyl lithium, LDA or lithium hexamethyldisilylamide.
  • a base such as butyl lithium, sec-butyl lithium, LDA or lithium hexamethyldisilylamide.
  • the ether-forming reaction between compounds of the formu_ae (XV) and (XVI) is typically performed in an inert solvent such as acetone or DMF, in a temperature range of ambient to 60°C, in the presence of a mild base.
  • Suitable values for L include tosylate, mesylate, triflate and halo, for example chloro or oromo.
  • compounds of the formulae (XV) and (XVI) may, for example, be reacted together in DMF, at ambient temperature m the presence of a base such as potassium carbonate.
  • the Mitsunobu reaction may be used (0. Synthesis, 1981, 1) .
  • the compounds of the formula (XV) and XVI may alternatively be reacted together using a phase transfer system.
  • reaction between compounds of tne formulae (XVII) and (XVIII) is conveniently carried out in the presence of a base, for example, lithium hydroxide or potassium tert-butoxide in an organic solvent such as an alcohol, for example, methanol.
  • a base for example, lithium hydroxide or potassium tert-butoxide
  • organic solvent such as an alcohol, for example, methanol.
  • the compounds of the formula (XVII) may ce prepared by reacting a compound of the formula (XVI) with a ccrtpound of the formula (XIX) : Q
  • reaction is conveniently carried out under standard conditions .-cnown in the art for such ether-forming reactions, for example, as described for the reaction between compounds of the formulae (ICY) an: (XVI) .
  • the compounds of the formulae (XI) , (XVI . (XVIII), (XIX), (XX) , (XXII) , (XXIV) , (XXVI) and (XXX) and starting materials for compounds of the formula (XV) are generally .nown m the art or can be made by methods analogous to or similar to those used in the examples or those known in the art for related compounds.
  • Optional substituents may be converted into other optional substituents.
  • an alkylthio group may be oxidised to an alkylsulphinyl or alkysulphonyl group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, or a bromo group converted to an alkylthio group.
  • an acyl group or alkyl group may be introduced into an activated benzene ring using Friedel-Crafts reactions, a formyl group by formylation with titanium tetrachloride and dichloromethyl ethyl ether, a nitro group by nitration with concentrated nitric acid concentrated sulphuirc acid and bromination with bromine or tetra(n-butyl)ammonium tribromide.
  • compounds of the formula (I) are antagonists of the pain enhancing effects of E-type prostaglandins and of value in the relief of mild to moderate pain which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarth ⁇ tis.
  • Certain properties of the compounds may be demonstrated using the test procedures set out below:- (a) an -v tro guinea pig lleum assay which assesses the inhibitory properties of a test compound against PGE -induced contractions of the ileum; ileum was immersed in oxygenated Krebs solution containing mdomethacm (4 ⁇ g/ml) and atrop e '1 ⁇ M) and which was maintained at 37 C; the ileum was subject to a tension of 1 g; a control dose response curve for PGE -induced contraction of the ileum was obtained; test compound (dissolved in dimethylsulphoxide) was added to the Krebs solution and a dose response curve for the PGE -induced contraction of the ileum in the presence of the test compound was obtained; the pA value for the test compound was calculated;
  • mice (b) an ln-vivo assay in mice which assesses the inhibitory properties of a test compound against abdominal constriction response induced by the mtrape ⁇ toneal administration of a noxicus agent such as dilute acetic acid or phenylbenzoquinone (hereinafter PBQ) using the procedure disclosed in European Patent Application No. C218077.
  • a noxicus agent such as dilute acetic acid or phenylbenzoquinone
  • Test (b) No overt toxicity or other untoward effects were noted in Test (b) when compounds of the formula I are administered at several multiples of their minimum inhibitory dose.
  • Prostaglandin receptors and in particular receptors for PGE have been tentatively characterised by Kennedy et al. 'Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, __! , 327) .
  • the known PGE antagonist SC-19220 blocks the effect of PGE on some tissues such as guinea pig ileum or dog fundus but not on other tissues such as the cat trachea or chick ileum. Those tissues wnich did possess SC-19220 sensitive mediated effects were said tc possess EP receptors. Based on this compounds of the present invention, possessing activity in Test (a), are EP antagonists.
  • a pharmaceutical composition which comprises a compound of the formula (I) or an -vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel, spray or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository or rectal spray; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, mtravascular or infusion) , for example a sterile aqueous or oily solution or suspension.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is a compound of the formula (I) or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • a ccording to a further feature of the invention there is provided the use of a compound of the formula I, or an m-vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the relief of pain in the animal (including human) body.
  • a method for the relief of pain in the animal (including human) body in need of such treatment which comprises administering to said bo ⁇ y an effective amount of a compound of the formula I, or an in-vivo nydrolysable ester or amide or a pharmaceutically-acceptable salt thereof.
  • a compound of the formula (I) is useful in treating the pain which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarth ⁇ tis.
  • a daily dose in the range for example, 0.1 mg to 75 mg per kg body weight is received, given if require ⁇ in divided doses.
  • lower doses will be administere ⁇ when a parenteral route is employed.
  • a dose in the range for example, 0.05 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg to 25 mg per kg body weight will be used.
  • the compounds of the formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man) , they are also useful whenever it is required to antagonise the effects of PGE at the EP receptor, based on test a) . Thus, they are useful as pharmacological standards for use m the development of new biological tests and m the search for new pharmacological agents.
  • the compounds of the formula I are of value in the treatment of certain inflammatory and non-inflammatory conditions which are currently treated with a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID) such as indomethacm, ketorolac, acetylsalicyclic acid, ibuprofen, sulindac, tolmetm and piroxicam or other analgesics such as paracetamol, tramadol, Codein or in some circumstances morphine.
  • NSAID cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug
  • a pharmaceutical composition which comprises a compound of tr.e formula J), or an in-vivo hydrolysable ester or amide or pharmaceutically-acceptable salt thereof, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.
  • the compounds of the invention may also be used with other anti-inflammatory agents such as an inhibitor cf the enzyme 5-lipoxygenase (such as those disclosed in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680).
  • an inhibitor cf the enzyme 5-lipoxygenase such as those disclosed in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680).
  • the compounds of the formula (I) may also be used in the treatment of conditions such as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate, steroids and penicillinamine, and in conditions such as osteoarthritis in combination with steroids.
  • antiarthritic agents such as gold, methotrexate, steroids and penicillinamine
  • the compounds of the present invention may also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, anti-degradative and/or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril.
  • degradative diseases for example osteoarthritis
  • chondroprotective, anti-degradative and/or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril.
  • compositions of the invention may in addition contain one or more other therapeutic or prophylactic agents known to be of value for the treatment of pain.
  • a known opiate pain-killer such as dextropropoxyphene, dehydrccodeine or codeine
  • an antagonist of other pain or inflammation mediators such as bradykinin, neurokinin and calcitonin gene related peptides (CGRP)
  • CGRP neurokinin and calcitonin gene related peptides
  • an alpha -adrenoceptor agonist such as bradykinin, neurokinin and calcitonin gene related peptides (CGRP)
  • CGRP neurokinin and calcitonin gene related peptides
  • an alpha -adrenoceptor agonist such as bradykinin, neurokinin and calcitonin gene related peptides (CGRP)
  • an alpha -adrenoceptor agonist such as bradykinin, neurokinin and calcitonin
  • the compounds of the present inventicn may also be administered in bone diseases such as osteoporosis alone or in combination with calcitonin and bisphosphonates and estrogens.
  • melting points are uncorrected and were determined using a Mettler S?62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, —ethanol, acetone, ether or hexane, alone or in admixture;
  • Example l The process described in Example l was repeated with the appropriate methyl 4- [3- (2-benzyloxyphenyl)propyl]benzoates to give the compounds described in the following table with appropriate modifications described in the notes below.
  • the methyl 4- [3- (2- benzyloxyphenyl)propyl]benzoate precursors were prepared from methyl 4- [3- (2-hydroxyphenyl)propyl]benzoate and the appropriate benzyl halide using the method described in Example 1 for the preparation of methyl 4- [3- (2-benzyloxyphenyl)propyl]benzoate.
  • a:- (4-Carboxyphenylmethyl)triphenylphosphonium bromide was prepared in the standard way from 4- (bromomethyl)benzoic acid and triphenylphosphine.
  • b:- (4-Carboxymethylphenylmethyl) triphenylphosphonium bromide was prepared in the standard way from 4- (bromomethyDphenylacetic acid and triphenylphosphine.
  • c - Methyl 4- [3- (2-hydroxy-5-nitrophenyl)propyl]benzoate was prepared from methyl 4- [3- (2-hydroxyphenyl)propyl]benzoate (see
  • Methyl 4- [2- (2-benzyloxyphenyl) ethyl] -3-fluorobenzoate was prepared as follows: (B) Methyl 3-fluoro-4-methylbenzoate was prepared from 3-fluoro-4-methylbenzoic acid by the process described in Example 6 for the synthesis of methyl 4- [3- (2-benzyloxy-5-hydroxyphenyl)propyl] - benzoate.
  • (B) Methyl 4- [2- (2-benzyloxyphenyl) - (E) -ethenyl] -2-hydroxy- benzcate was prepared as follows :
  • Example 1 (A) A similar process to that of Example 1 (A) with the appropriate methyl benzoates was used to prepare the compounds in the following table with appropriate modifications described in the footnotes.
  • Methyl 4- [2- (2-benzyloxy-5-methanethiophenyl) ethenyl] -2- hydroxybenzoate was prepared from 2-benzyloxy-4-methanethio- benzaldehyde and 4-methoxycarbonyl-3-acetoxybenzyltriphenylphosphonium bromide using a similar method to that of Example 8, (E) in the course of which the acetate group was hydrolysed. The required E isomer was obtained from the mixture of Z and E isomers by separation using MPLC on silica gel. d:- See second part of note (c) .
  • 5-hydroxymethyl-2- pyridinecarboxylate The required phosphonium salt was prepared from methyl 5-methanesulphonyloxymethyl-2-pyridine- carboxylate which was made using standard procedures.
  • Methyl 4- [3- (2-hydroxy-6-methoxyphenyl)prcpyl]benzoate was converted to methyl 4- [3- (2-benzyloxy-6-methoxypnenyl)propyl]benzoate by a similar method to that of Example 1, (B) .
  • Methyl 2- [2-benzyloxy-5- methanesulphonylphenethyl] -5- -.ethoxycarbonyl) - pyr ⁇ d ⁇ ne-1-oxide was obtained as a side product from this reaction, ac:- Methyl 4- [2- (2-benzyloxyphenyl)ethenyl] -3-hydroxybenzoate was prepared from methyl 2-acetoxy-4-methylbenzoate and 2-benzyloxybenzaldehyde using similar processes to those described in
  • Example 8 It was purified by MPLC on silica gel eluting with
  • Example 84 (A) was repeated with the appropriate nitriles to give the compounds described in the following table:
  • nitrile precursors were prepared from the corresponding primary amides as exemplified by the following method: Trifluoroacetic anhydride (0.75 ml) was added to a mixture of 4- [2-benzyloxyphenethyl] -3-bromobenzam ⁇ de (1.46 g) and pyridine o (0.86 ml) in THF at -20 C. The mixture was stirred at ambient temperature for 18 hours, diluted with ethyl acetate and washed with water, dried (MgSO ) , filtered and evaporated to dryness.
  • Trifluoroacetic anhydride (0.75 ml) was added to a mixture of 4- [2-benzyloxyphenethyl] -3-bromobenzam ⁇ de (1.46 g) and pyridine o (0.86 ml) in THF at -20 C. The mixture was stirred at ambient temperature for 18 hours, diluted with ethyl acetate and washed with water, dried
  • N-cyanometnyl-6- [ -benzyloxy-5-bromophenethyl] -2- oxo-lH-pyr ⁇ dme-3-carboxam ⁇ de was prepared from 6- [2-benzyloxy-5- bromophenethyl] -2-oxo-lH-pyr ⁇ d ⁇ ne-3-carboxyl ⁇ c acid by method.
  • Benzyl 4- [3- (2-hydroxy-4- cyanophenyl)propyl)benzoate was prepared as follows: - 4- [3- ( 2-Hydroxy-4-cyanophenyl)propyl)benzoic acid was converted to benzyl 4- [3- (2-benzyloxy-4-cyanophenyl)propylbenzoate by a similar method to that of Example 1, (I) using two equivalents of benzyl bromide and potassium carbonate.
  • N- (3-allyloxyphenyl)acetamide (13.2 g) prepared by a similar method to that of Example 2, Footnote c (A) , from N- (3-hydroxyphenyl)acetamide, in Ph O (100 ml) was heated at 250 C for 10 minutes, cooled and diluted with hexane (100 ml) to give crystals. The crystals were re-crystallised from ethyl acetate. The liquors were evaporated and dissolved in 0.2M aqueous NaOH, filtered though Celite, and acidified with M aqueous HCl solution to give N- (4-allyl-3- hydroxyphenyl, acetamide (3.6 g) mpt. 164-165 C.
  • the ethyl ester was prepared as follows:-
  • Oxalyl chloride (3.27g) was added dropwise to a stirred solution of 4- [3- (2-benzyloxyphenyl)propyl]benzene carboxylic acid

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IL115577A0 (en) 1996-01-19
GB9420557D0 (en) 1994-11-30
DE69514087T2 (de) 2000-04-27
AU3616295A (en) 1996-05-06
WO1996011902A1 (en) 1996-04-25
EP0733033B1 (de) 1999-12-22
ZA958622B (en) 1996-04-12
US5811459A (en) 1998-09-22
JPH09511529A (ja) 1997-11-18
DE69514087D1 (de) 2000-01-27

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